@article{pmid39778789,

title = {Virus-mediated delivery of single-chain antibody targeting TDP-43 protects against neuropathology, cognitive impairment and motor deficit caused by chronic cerebral hypoperfusion},

author = {Anna Ania Chami and Claude Gravel and Yuan Cheng Weng and Jasna Kriz and Jean-Pierre Julien},

doi = {10.1016/j.expneurol.2025.115138},

issn = {1090-2430},

year  = {2025},

date = {2025-03-01},

journal = {Exp Neurol},

volume = {385},

pages = {115138},

abstract = {Chronic cerebral hypoperfusion induced by permanent unilateral common carotid artery occlusion in mice was recently found to induce an age-dependent formation of insoluble cytoplasmic TDP-43 aggregates reminiscent of pathological changes found in human vascular dementia. In this model, the gradual deregulation of TDP-43 homeostasis in cortical neurons was associated with marked cognitive and motor deficits. To target the TDP-43-mediated toxicity in this model, we generated an adeno-associated virus vector encoding a single-chain antibody against TDP-43, called scFv-E6, designed for pan-neuronal transduction following intravenous administration. Injected prior to brain hypoperfusion, this tonic virus-mediated delivery of the scFv-E6 antibody reduced formation of cytoplasmic TDP-43 aggregates in cortical neurons, boosted levels of autophagy markers and attenuated microgliosis. Moreover, the novel object recognition and grip strength tests revealed that neuronal expression of scFv-E6 prevented the cognitive impairment and loss of motor performance caused by two-months of cerebral hypoperfusion. The robust protective effects of scFv-E6 antibody in this model suggest a key role of TDP-43 in neuronal damage and symptom phenotypes caused by chronic cerebral hypoperfusion. Accordingly, TDP-43 should be considered as a new therapeutic target in drug development, including antibody approaches, for treatment of vascular dementia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41343582,

title = {Comprehensive analysis platform to understand, remedy, and eliminate amyotrophic lateral sclerosis (CAPTURE ALS): Study protocol for a Canadian multicenter, multimodal, longitudinal observational study},

author = {Natalie Saunders and Claire Magnussen and HyungMo Kang and Mathieu Blais and Harpreet Bhinder and Gerald Pfeffer and Shelagh K Genuis and Liziane Bouvier and Tanushka Anand and Rida Abou-Haidar and Agessandro Abrahao and Marie-Noëlle Boivin and Robert Bowser and Tania Bubela and Julia Chiappini and Samir Das and Avnit Dhanoa and Nicolas Dupré and Alan Evans and Nicolas Ferry and Yvonne Frater and Angela Genge and Simon J Graham and Russell Greiner and Yasser Iturria Medina and Wendy S Johnston and Kelvin E Jones and Jason Karamchandani and Jasna Kriz and Westerly Luth and Geneviève Matte and Ekaterina Rogaeva and Janice Robertson and Peter Seres and Fred Tam and David Taylor and Clémence Tremblay-Desbiens and Christine Vande Velde and Yana Yunusova and Lorne Zinman and Sanjay Kalra},

doi = {10.1371/journal.pone.0332430},

issn = {1932-6203},

year  = {2025},

date = {2025-01-01},

journal = {PLoS One},

volume = {20},

number = {12},

pages = {e0332430},

abstract = {BACKGROUND: The marked heterogeneity of Amyotrophic Lateral Sclerosis (ALS) combined with a lack of biomarkers are key contributing factors to the lack of disease-modifying treatments. The Comprehensive Analysis Platform to Understand Remedy and Eliminate ALS (CAPTURE ALS) is a Canadian platform designed to create the most comprehensive picture of people living with ALS with the objective of facilitating ALS research initiatives worldwide.nnOBJECTIVES: The main aims of CAPTURE ALS include: (1) to characterize ALS and healthy controls with biosamples and data in order to provide the most comprehensive picture of individuals living with ALS to date; (2) to create a de-identified database and biosample repository linked to detailed clinical information; and (3) to develop and implement an inclusive and transparent participant engagement strategy to be active throughout all stages of CAPTURE ALS.nnMETHODS/RESULTS: CAPTURE ALS is a prospective, multicenter, observational, longitudinal study. People living with ALS, or a related disease and healthy controls undergo a harmonized protocol including the collection of detailed clinical information, neurological and cognitive examination, speech recording, advanced magnetic resonance imaging, and biosampling. Data and samples are stored in a biobank operating under an open science governance framework. An inclusive and transparent participant engagement strategy was designed and implemented throughout all stages of CAPTURE ALS. Four sites are operating in the consortium with a fifth being onboarded. The target enrollment is 120 affected participants and 50 controls, with the first participant visit having occurred in March 2022. Recruitment is ongoing.nnDISCUSSION: CAPTURE ALS is a scalable clinical research platform that connects scientists and patients to facilitate efficient translational research. The unique and deeply phenotyped data and biosamples are a global resource towards the development of biomarkers and understanding ALS biology. This study is registered at clinicaltrials.gov (NCT: NCT05204017).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39857801,

title = {Repetitive Mild but Not Single Moderate Brain Trauma Is Associated with TAR DNA-Binding Protein 43 Mislocalization and Glial Activation in the Mouse Spinal Cord},

author = {Tamara Janković and Jelena Rajič Bumber and Nika Gržeta Krpan and Petra Dolenec and Marc Jaeger and Jasna Kriz and Gordana Župan and Kristina Pilipović},

doi = {10.3390/biomedicines13010218},

issn = {2227-9059},

year  = {2025},

date = {2025-01-01},

journal = {Biomedicines},

volume = {13},

number = {1},

abstract = {: Traumatic brain injury (TBI) occurs after a sudden mechanical force to the skull and represents a significant public health problem. Initial brain trauma triggers secondary pathophysiological processes that induce structural and functional impairment of the central nervous system, even in the regions distant to the lesion site. Later in life, these changes can be manifested as neurodegenerative sequalae that commonly involve proteinopathies, such as transactive DNA-binding protein 43 (TDP-43). The progression of pathophysiological changes to the spinal cord motor neurons has been detected after repetitive TBI, while such changes have been less investigated after single TBI. : Single TBI was applied over the left parietal cortex of mice by using the lateral fluid percussion injury apparatus and a separate cohort of animals received repetitive mild TBI by weight drop apparatus, with two mild injuries daily, for five days in a row. Mice were sacrificed after single moderate or last mild TBI and their spinal cords were prepared for the analyses. For both types of injury, sham-injured mice were used as a control group. : Here, we found an early formation of toxic phosphorylated TDP-43 species on the 3rdday post-injury which, together with TDP-43 cytoplasmic translocation, remained present in the subacute period of 14 days after repetitive mild but not single moderate TBI. During the subacute period following a repetitive brain trauma, we found an increased choline acetyltransferase protein expression and significant microgliosis in the cervical part of the spinal cord, which was not detected after single TBI. Astrogliosis presented similarly after both experimental procedures. : This study demonstrates the differences in the spinal cord TDP-43 pathology and inflammation, depending on the brain trauma type, and may contribute to the development of targeted therapeutic strategies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38577970,

title = {Chronically activated microglia in ALS gradually lose their immune functions and develop unconventional proteome},

author = {Romina Barreto-Núñez and Louis-Charles Béland and Hejer Boutej and Vincent Picher-Martel and Nicolas Dupré and Luis Barbeito and Jasna Kriz},

doi = {10.1002/glia.24531},

issn = {1098-1136},

year  = {2024},

date = {2024-07-01},

journal = {Glia},

volume = {72},

number = {7},

pages = {1319--1339},

abstract = {Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1-G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age-matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo. Proteome analysis revealed a development of two distinct molecular signatures at early and advanced stages of disease. While at early stages of disease, we identified several proteins implicated in microglia immune functions such as GPNMB, HMBOX1, at advanced stages of disease microglia signature at protein level was characterized with a robust upregulation of several unconventional proteins including rootletin, major vaults proteins and STK38. Upregulation of GPNMB and rootletin has been also found in the spinal cord samples of sporadic ALS. Remarkably, the top biological functions of microglia, in particular in the advanced disease, were not related to immunity/immune response, but were highly enriched in terms linked to RNA metabolism. Together, our results suggest that, over the course of disease, chronically activated microglia develop unconventional protein signatures and gradually lose their immune identity ultimately turning into functionally inefficient immune cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38790979,

title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS},

author = {Pooja Shree Mishra and Daniel Phaneuf and Hejer Boutej and Vincent Picher-Martel and Nicolas Dupre and Jasna Kriz and Jean-Pierre Julien},

doi = {10.3390/biomedicines12051017},

issn = {2227-9059},

year  = {2024},

date = {2024-05-01},

journal = {Biomedicines},

volume = {12},

number = {5},

abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38196192,

title = {Targeting SRSF3 restores immune mRNA translation in microglia/macrophages following cerebral ischemia},

author = {Reza Rahimian and Revathy Guruswamy and Hejer Boutej and Pierre Cordeau and Yuan Cheng Weng and Jasna Kriz},

doi = {10.1016/j.ymthe.2024.01.004},

issn = {1525-0024},

year  = {2024},

date = {2024-03-01},

journal = {Mol Ther},

volume = {32},

number = {3},

pages = {783--799},

abstract = {We recently described a novel ribosome-based regulatory mechanism/checkpoint that controls innate immune gene translation and microglial activation in non-sterile inflammation orchestrated by RNA binding protein SRSF3. Here we describe a role of SRSF3 in the regulation of microglia/macrophage activation phenotypes after experimental stroke. Using a model-system for analysis of the dynamic translational state of microglial ribosomes we show that 24 h after stroke highly upregulated immune mRNAs are not translated resulting in a marked dissociation of mRNA and protein networks in activated microglia/macrophages. Next, microglial activation after stroke was characterized by a robust increase in pSRSF3/SRSF3 expression levels. Targeted knockdown of SRSF3 using intranasal delivery of siRNA 24 h after stroke caused a marked knockdown of endogenous protein. Further analyses revealed that treatment with SRSF3-siRNA alleviated translational arrest of selected genes and induced a transient but significant increase in innate immune signaling and IBA1+ immunoreactivity peaking 5 days after initial injury. Importantly, delayed SRSF3-mediated increase in immune signaling markedly reduced the size of ischemic lesion measured 7 days after stroke. Together, our findings suggest that targeting SRSF3 and immune mRNA translation may open new avenues for molecular/therapeutic reprogramming of innate immune response after ischemic injury.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38104136,

title = {Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome},

author = {Shabana M Shaik and Yajun Cao and Joseph V Gogola and Hemraj B Dodiya and Xulun Zhang and Hejer Boutej and Weinong Han and Jasna Kriz and Sangram S Sisodia},

doi = {10.1186/s13024-023-00668-7},

issn = {1750-1326},

year  = {2023},

date = {2023-12-01},

journal = {Mol Neurodegener},

volume = {18},

number = {1},

pages = {95},

abstract = {BACKGROUND: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear. Here, by generating 'APPPS1-21-CD11br' reporter mice, we investigated the translational state of microglial/macrophage ribosomes during their phenotypic transition and in a sex-specific manner.nnMETHODS: Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br males and females were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial/macrophage polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry and label-free quantification was used to identify newly synthesized peptides isolated from polysomes.nnRESULTS: We show that ABX-treatment leads to decreased Aβ levels in male APPPS1-21-CD11br mice with no significant changes in females. We identified microglial/macrophage polypeptides involved in mitochondrial dysfunction and altered calcium signaling that are associated with Aβ-induced oxidative stress. Notably, female mice also showed downregulation of newly-synthesized ribosomal proteins. Furthermore, male mice showed an increase in newly-synthesized polypeptides involved in FcγR-mediated phagocytosis, while females showed an increase in newly-synthesized polypeptides responsible for actin organization associated with microglial activation. Next, we show that ABX-treatment resulted in substantial remodeling of the epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards a neuroprotective phenotype that promotes Aβ clearance, microglia in ABX-treated female mice exhibited loss of energy homeostasis due to persistent mitochondrial dysfunction and impaired lysosomal clearance that was associated with inflammatory phenotypes.nnCONCLUSIONS: Our studies provide the first snapshot of the translational state of microglial/macrophage cells in a mouse model of Aβ amyloidosis that was subject to ABX treatment. ABX-mediated changes resulted in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance in a sex-specific manner. This microglial plasticity to support neuro-energetic homeostasis for its function based on sex paves the path for therapeutic modulation of immunometabolism for neurodegeneration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37371694,

title = {Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder},

author = {Fabiola De Marchi and Toni Franjkic and Paride Schito and Tommaso Russo and Jerneja Nimac and Anna A Chami and Angelica Mele and Lea Vidatic and Jasna Kriz and Jean-Pierre Julien and Gordana Apic and Robert B Russell and Boris Rogelj and Jason R Cannon and Marco Baralle and Federica Agosta and Silva Hecimovic and Letizia Mazzini and Emanuele Buratti and Ivana Munitic},

doi = {10.3390/biomedicines11061599},

issn = {2227-9059},

year  = {2023},

date = {2023-05-01},

journal = {Biomedicines},

volume = {11},

number = {6},

abstract = {Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36982140,

title = {Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis},

author = {Vincent Picher-Martel and Hejer Boutej and Alexandre Vézina and Pierre Cordeau and Hannah Kaneb and Jean-Pierre Julien and Angela Genge and Nicolas Dupré and Jasna Kriz},

doi = {10.3390/ijms24065065},

issn = {1422-0067},

year  = {2023},

date = {2023-03-01},

journal = {Int J Mol Sci},

volume = {24},

number = {6},

abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune-metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune-metabolic homeostasis in ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36651748,

title = {Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease},

author = {Sonia M Vallabh and Dan Zou and Rose Pitstick and Jill O'Moore and Janet Peters and Derek Silvius and Jasna Kriz and Walker S Jackson and George A Carlson and Eric Vallabh Minikel and Deborah E Cabin},

doi = {10.1128/jvi.01672-22},

issn = {1098-5514},

year  = {2023},

date = {2023-02-01},

journal = {J Virol},

volume = {97},

number = {2},

pages = {e0167222},

abstract = {Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective  against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to >20 months of age. Vacuolization and PrP deposition were observed in some brain regions in a subset of mutant animals but appeared to be unable to carry the weight of a primary endpoint in a therapeutic study. We conclude that not all animal models of prion disease are suited to well-powered therapeutic efficacy studies, and care should be taken in choosing the models that will support drug development programs.  There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program. While the study of prion disease benefits from excellent animal models because prions naturally afflict many different mammals, different models have different capabilities and limitations. Here, we conducted a therapeutic efficacy study of the drug candidate anle138b in mouse models with two of the most common mutations that cause genetic prion disease. In a more typical model where prions are injected directly into the brain, we found anle138b to be effective. In the genetic models, however, the animals never reached a clear, measurable point of disease onset. We conclude that not all prion disease animal models are ideally suited to drug efficacy studies, and well-defined, quantitative disease metrics should be a priority.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}